Highlights from Recent Cancer Literature
Journal: Cancer Research (2016)

Recurrent mutations in the N-terminus of histone H3 include K27M in high-grade glioma and K36M in chondroblastoma. Fang and colleagues (1) and Lu and colleagues (2) introduced the K36M mutation into either immortalized human chondrocytes or mesenchymal progenitor cells, reducing global K36 methylation and altering gene expression to restrict cell differentiation. Strikingly, both studies show inhibition of four SET-domain lysine methyltransferases by K36M-mutated nucleosomes as the mechanism leading to epigenetic reprogramming and inhibition of cell differentiation. Although loss of K36 methylation led to increased K27 methylation, introduction of the K27M mutation had no effect on chondrocyte differentiation, implicating a tissue-specific mechanism inhibiting cell differentiation. Lu and colleagues also identified undifferentiated sarcomas harboring recurrent mutations in K36M, widening the spectrum of histone tail mutations in human malignancies.1. Fang D, Gan H, Lee JH, Han J, Wang Z, Riester SM, et al. The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas. Science 2016;352:1344–8.2. Lu C, Jain SU, Hoelper D, Bechet D, Molden RC, Ran L., et al. Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape. Science 2016;352:844–9.Patients with advanced neuroendocrine tumors (NET) have a poor prognosis and lack treatment options. Klempner and colleagues characterized 109 colorectal NETs. Nine percent showed recurrent somatic BRAF alterations (80% with BRAFV600E), the first report of this mutation in high-grade NETs. BRAF mutations were mutually exclusive with oncogenic RAS mutations. Two patients with rectal high-grade NETs achieved a robust antitumor response to dual BRAF-MEK inhibition, a combination active in advanced BRAF-mutant colorectal adenocarcinoma, along with a concomitant decrease in BRAFV600E urinary circulating tumor DNA. This report represents the largest dataset of colorectal NETs subjected to next-generation sequencing for molecular profiling, provides opportunities for development of rational targeted therapy, and supports ongoing genomic profiling efforts to identify druggable molecular vulnerabilities.Klempner SJ, Gershenhorn B, Tran P, Lee TK, Erlander MG, Gowen K, et al. BRAFV600E mutations in high-grade colorectal neuroendocrine tumors may predict responsiveness to BRAF-MEK combination therapy. Cancer Discov 2016;6:594–600.Metastatic castrate-resistant prostate cancer (CRPC) represents the most lethal form of prostate cancer. Kaushik and colleagues identified novel metabolic reprogramming that occurs during the transition from normal prostate to CRPC. Genes and metabolic products from the hexosamine biosynthetic pathway (HBP), a versatile energy-sensing pathway downstream of glycolysis, were elevated in prostate cancer compared with normal prostate cells. Interestingly, the HBP was diminished in CRPC compared with hormone-dependent prostate cancer. Genetic and pharmacologic modulation of the HBP changed prostate cancer proliferation and aggressiveness in vitro and in vivo via PI3K-AKT and SP1-regulated pathways. These new findings open up the exciting possibility that therapies directed at modulating HBP metabolic reprogramming may be utilized in CRPC.Kaushik AK, Shojaie A, Panzitt K, Sonavane R, Venghatakrishnan H, Manikkam M, et al. Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer. Nat Commun 2016;7:11612. doi: 10.1038/ncomms11612.Some subtypes of acute myeloid leukemia (AML) show high expression of FLT3 and are associated with unfavorable prognosis. Jiang and colleagues developed a novel targeted nanoparticle system, FLT3 ligand (FLT3L)-conjugated G7 poly(amidomine) (PAMAM) nanosized dendriplex encapsulating miR-150, to specifically target FLT3-overexpressing AML. Of note, miR-150 is a known tumor-suppressor and a negative regulator of FLT3. In vitro, these nanoparticles could selectively and efficiently target FLT3-overexpressing AML cells, inhibiting cell viability/growth and promoting apoptosis. These findings were validated in vivo. Nanoparticles significantly inhibited disease progression without affecting normal hematopoiesis. This study also provides conceptual advances in the field of nanoparticle design/application as well as targeted leukemia/cancer therapy for development of new therapies against FLT3-overexpressing AML.Jiang, X, Bugno J, Hu Chao, Yang Y, Herold T, Qi J, et al. Eradication of acute myeloid leukemia with FLT3 ligand-targeted miR-150 nanoparticles. Cancer Research; Published OnlineFirst June 8, 2016; doi: 10.1158/0008-5472.CAN-15-2949.Glycosaminoglycans (GAG), polysaccharides attached to core proteoglycans proteins, play critical roles in signaling and cell-extracellular matrix interactions. Using gene expression data from The Cancer Genome Atlas, clustering algorithms, and protein level data, Gatto and colleagues demonstrated that clear cell renal cell carcinoma, but not other epithelial carcinomas, showed coordinated regulation of GAG biosynthesis—upregulating chondroitin sulfate biosynthetic genes and downregulating heparan sulfate biosynthetic genes. These alterations were most pronounced in metastatic disease. They hypothesized that alterations in GAG structure and amount might be detectable in body fluids and went on to identify these metabolites in plasma and urine. If confirmed in blinded studies involving larger and more complex patient cohorts, these data suggest GAG amount and composition in body fluids have the potential as a biomarker of disease.Gatto F, Volpi N, Nilsson H, Nookaew I, Maruzzo M, Roma A, et al. Glycosaminoglycan profiling in patients' plasma and urine predicts the occurrence of metastatic clear cell renal cell carcinoma. Cell Rep 2016;15:1822–36.The Genomics of Drug Sensitivity in Cancer (GDSC) and the Cancer Cell Line Encyclopedia (CCLE) collectively characterized &gt;1,000 cell lines and ∼150 anticancer agents. A subsequent independent re-analysis of these two large screening studies found little concordance between the two large datasets. In an effective tie-breaking move, the Genentech Cell Line Screening Initiative (gCSI) independently assayed 410 cell lines against 16 anticancer agents and compared their findings with those of the GDSC and CCLE. When robust drug response statistics were used, gCSI investigators achieved concordance and consistency, with technical issues regarding cell culturing conditions and differences in cell viability assays contributing to some of the variability between GDSC and CCLE studies. Findings by Harvety and colleagues “reset the potential of large cell line panels for characterization of heterogeneous response to anticancer agents and therapeutics.”Haverty PM, Lin E, Tan J, Yu Y, Lam B, Lianoglou S, et al. Reproducible pharmacogenomic profiling of cancer cell line panels. Nature 2016;533:333–7.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.